Katja[a]
Clinical outcome and distribution measure of a recombinant chimeric protein composed of transforming growth factor alpha and a mutated Pseudomonas exotoxin (TP-38) via convection-enhanced microinfusion on a phase I study for malignant brain tumor
J. H. Sampson, G. Akabani, G. Archer, M. Berger, A. Friedman, H. S. Friedman, S. Marcus, D. Reardon, D. D. Bigner, I. Pastan; Duke Univ Med Ctr, Durham, NC; University of California, San Francisco, San Francisco, CA; IVAX, Miami, FL; Duke Univ Med Ctrr, Durham, NC; National Cancer Institute, Bethesda, MD
The primary objective of this Phase I trial is to determine the maximum tolerated dose (MTD) of a recombinant chimeric protein (TP-38) composed of the EGFR binding ligand TGF-alpha and a mutated form of the Pseudomonas exotoxin, PE-38, infused intracerebrally in a volume of 40 mL over 55 hours via catheters placed stereotactically. Secondary objectives included determining therapeutic activity and to assess achieved distribution. To date, 20 patients have been treated including 16 patients with recurrent GBM, and single patients with gliosarcoma, anaplastic astrocytoma, anaplastic oligodendroglioma, or metastatic spindle cell sarcoma. Median age is 53.5 years (range, 21-68 years) and all patients had a KPS between 60% and 100%. Median prior chemotherapeutic agents was 3.5 (range, 1-7). Six patients received TP-38 at the initial dose level of 25 ng/ml (1 mcg), 8 received 50 ng/ml (2 mcg) and 6 received 100 ng/ml (4 mcg). The only DLT occurred in a patient at the 100 ng/ml level and involved grade 4 generalized weakness. No systemic toxicity occurred. The MTD has not been reached. Overall median survival is 23 weeks (range, 1.1-83.1 weeks). Four patients are alive with progressive disease 27-34 weeks from TP-38. Five patients are alive without progressive disease between 20 and 83 weeks TP-38. Two patients achieved a partial response including one treated at the 100 ng/ml dose level and a patient treated at the 25 ng/mL dose level for a multi-recurrent bifrontal GBM who remains without evidence of active tumor 83 weeks after TP-38. In 4/02 the protocol was amended to combine the TP-38 infusion with 100 mCi of non-therapeutic 123I-labeled albumin. To date, 8 patients have received the TP-38/123I-albumin infusion and undergone analysis with SPECT imaging to evaluate the 123I-albumin distribution. Preliminary analysis reveals that the volume of distribution can be several fold greater than the infusion volume. However this analysis also suggests that some patients failed due to inadequate TP-38 distribution.
ASCO 2003 Abstract No: 397 Category: CNS Tumors